The sturctures of the human, mouse and guinea pig insulin genes will be studied by DNA sequencing. These structures will be correlated to diabetes, particularly in the human case. The control of insulin biosynthesis via changes in the concentration of its messenger RNA will be studied in rats and mice. A number of specific questions will be answered: Do the inserted DNA sequences which occur near the insulin gene in the human genome relate either to juvenile or maturity onset diabetes? Are the inserted sequences related to one another? Are they stably inherited in a mendelian fashion or are they somatically generated? What are the actual sequences of some of these insertions and of the sites at which they occur? Do the two nonallelic mouse insulin genes have the same intervening sequence pattern and conserved 5'-noncoding regions as those found for the two rat genes? Do the mouse genes lie on the same chromosome? Are they clustered together? Are they transcribed from the same DNA strand? Is insulin biosynthesized at low levels in nonpancreatic tissues? Is such extrapancreatic insulin in the guinea pig coded for by a second insulin gene which differs considerably from the pancreatic gene? Does the pancreas type guinea pig gene show conserved noncoding (perhaps regulatory) sequences? Does the concentration of insulin mRNA in the Beta cell vary significantly in response to physiological changes, and with what time course? Are the two insulin mRNAs of rats and mice distinguishable and do they show noncoordinate regulatory responses? How have the insulin genes evolved, particularly how have the murid genes been duplicated, and how has the guinea pig gene (whose protein is highly diverged from other mammalian insulins) changed? The studies will allow a correlation of insulin gene structure, insulin mRNA expression, and physiological states in genetically well defined human and rodent populations.